The mechanisms of incomplete penetrance of risk-modifying impacts of apolipoprotein E (APOE) ε2 and ε4 alleles on Alzheimer’s disease (AD) have not been fully understood. We performed genome-wide analysis of differences in linkage disequilibrium (LD) patterns between 6,136 AD-affected and 10,555 AD-unaffected subjects from five independent studies to explore whether the association of the APOE ε2 allele (encoded by rs7412 polymorphism) and ε4 allele (encoded by rs429358 polymorphism) with AD was modulated by autosomal polymorphisms. The LD analysis identified 24 (mostly inter-chromosomal) and 57 (primarily intra-chromosomal) autosomal polymorphisms with significant differences in LD with either rs7412 or rs429358, respectively, between AD-affected and AD-unaffected subjects, indicating their potential modulatory roles. Our Cox regression analysis showed that minor alleles of four inter-chromosomal and ten intra-chromosomal polymorphisms exerted significant modulating effects on the ε2- and ε4-associated AD risks, respectively, and identified ε2-independent (rs2884183 polymorphism, 11q22.3) and ε4-independent (rs483082 polymorphism, 19q13.32) associations with AD. Our functional analysis highlighted ε2- and/or ε4-linked processes affecting the lipid and lipoprotein metabolism and cell junction organization which may contribute to AD pathogenesis. These findings provide insights into the ε2- and ε4-associated mechanisms of AD pathogenesis, underlying their incomplete penetrance.

载脂蛋白 E ( APOE ) ε2 和 ε4 等位基因对阿尔茨海默病 (AD)的风险修正影响的不完全外显率机制尚未完全了解。我们对来自五项独立研究的 6,136 名受 AD 影响和 10,555 名未受 AD 影响的受试者之间的连锁不平衡 (LD) 模式差异进行了全基因组分析，以探讨APOE的关联是否AD 的 ε2 等位基因（由 rs7412 多态性编码）和 ε4 等位基因（由 rs429358 多态性编码）受常染色体多态性调节。LD 分析确定了 24 个（主要是染色体间的）和 57 个（主要是染色体内的）常染色体多态性，在受 AD 影响和未受 AD 影响的受试者之间，分别具有 rs7412 或 rs429358 的 LD 显着差异，表明它们具有潜在的调节作用。我们的 Cox 回归分析表明，四个染色体间和十个染色体内多态性的次要等位基因分别对 ε2 和 ε4 相关的 AD 风险产生显着调节作用，并确定了 ε2 独立（rs2884183 多态性，11q22.3）和ε4 独立（rs483082 多态性，19q13.32）与 AD 的关联。我们的功能分析强调了影响脂质和脂蛋白代谢和细胞连接组织的 ε2 和/或 ε4 相关过程，这可能有助于 AD 发病机制。这些发现提供了对 AD 发病机制的 ε2 和 ε4 相关机制的见解，这是它们不完全外显率的基础。